{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T14:11:27Z","timestamp":1792591887936,"version":"4.5.0"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T00:00:00Z","timestamp":1651190400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>This study aimed to examine the associations with epidemiological, behavioral and clinical parameters of IgG antibody responses against the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after immunization with two doses of the BNT162b2 vaccine in a cohort of healthcare workers (HCWs, n = 439) in Greece. We used a mixed effects model to investigate the potential associations of antibody levels one and three months after vaccination and examined by bootstrapping t-tests the putative effects of gender and age for each period. We also employed exact tests of independence in R \u00d7 C contingency tables to explore associations between behavioral and gender variables with vaccinations side effects. We found significant differences between males and females as well as between subjects in the youngest (21\u201330 years) and the older age groups in both study periods. We also detected a decrease in titers with age and time. Males had steeper elimination rates across the age span in both periods, in contrast to females who exhibited a softer elimination titer rate with age in the first period and almost constant titers in the second. Concerning side effects, we found a significant association between pain at the injection site and female sex. Hence, our real-world data analyses revealed potentially important clues into the associations of antibody responses to SARS-CoV-2 spike. We discuss the importance of these findings in view of current mass vaccination perspectives and provide useful clues for the design and optimal timing of booster doses for COVID-19.<\/jats:p>","DOI":"10.1371\/journal.pone.0266958","type":"journal-article","created":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T17:34:20Z","timestamp":1651253660000},"page":"e0266958","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":42,"title":["Age and sex associations of SARS-CoV-2 antibody responses post BNT162b2 vaccination in healthcare workers: A mixed effects model across two vaccination periods"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7666-9198","authenticated-orcid":true,"given":"Cleo","family":"Anastassopoulou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitra","family":"Antoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6065-7368","authenticated-orcid":true,"given":"Yiannis","family":"Manoussopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis","family":"Stefanou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Argyropoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Vrioni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0656-4715","authenticated-orcid":true,"given":"Athanasios","family":"Tsakris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,4,29]]},"reference":[{"key":"pone.0266958.ref001","first-page":"495","article-title":"BNT162b2 mRNA COVID-19 Vaccine","volume":"81","author":"YN Lamb","year":"2021","journal-title":"First Approval. Drugs"},{"key":"pone.0266958.ref002","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1056\/NEJMoa2034577","article-title":"Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine","volume":"383","author":"FP Polack","year":"2020","journal-title":"The New England journal of medicine"},{"key":"pone.0266958.ref003","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1056\/NEJMoa2101765","article-title":"BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting","volume":"384","author":"N Dagan","year":"2021","journal-title":"N Engl J Med"},{"key":"pone.0266958.ref004","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/S0140-6736(21)00448-7","article-title":"Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients","volume":"397","author":"S Amit","year":"2021","journal-title":"The Lancet"},{"key":"pone.0266958.ref005","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/S2213-2600(21)00220-4","article-title":"BNT162b2 COVID-19 vaccine and correlates of humoral immune responses and dynamics: a prospective, single-centre, longitudinal cohort study in health-care workers","volume":"9","author":"Y Lustig","year":"2021","journal-title":"The Lancet Respiratory Medicine"},{"key":"pone.0266958.ref006","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1016\/S0140-6736(21)00782-0","article-title":"Correlates of protection from SARS-CoV-2 infection","volume":"397","author":"F. Krammer","year":"2021","journal-title":"The Lancet"},{"key":"pone.0266958.ref007","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1056\/NEJMoa2034545","article-title":"Antibody Status and Incidence of SARS-CoV-2 Infection in Health Care Workers","volume":"384","author":"SF Lumley","year":"2021","journal-title":"N Engl J Med"},{"key":"pone.0266958.ref008","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1515\/cclm-2021-0339","article-title":"Comprehensive assessment of humoral response after Pfizer BNT162b2 mRNA Covid-19 vaccination: a three-case series","volume":"59","author":"E Danese","year":"2021","journal-title":"Clinical Chemistry and Laboratory Medicine (CCLM)"},{"key":"pone.0266958.ref009","doi-asserted-by":"crossref","first-page":"3991","DOI":"10.1038\/s41467-021-24285-4","article-title":"COVID-19 mRNA vaccine induced antibody responses against three SARS-CoV-2 variants","volume":"12","author":"P Jalkanen","year":"2021","journal-title":"Nat Commun"},{"key":"pone.0266958.ref010","doi-asserted-by":"crossref","first-page":"5337","DOI":"10.1016\/j.vaccine.2021.08.025","article-title":"Kinetics of SARS-CoV-2 anti-S IgG after BNT162b2 vaccination","volume":"39","author":"D Grupel","year":"2021","journal-title":"Vaccine"},{"key":"pone.0266958.ref011","article-title":"Age-dependent immune response to the Biontech\/Pfizer BNT162b2 COVID-19 vaccination","author":"L M\u00fcller","year":"2021","journal-title":"Clinical Infectious Diseases"},{"key":"pone.0266958.ref012","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"SL Klein","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"pone.0266958.ref013","article-title":"Association of total and neutralizing SARS-CoV-2 spike -receptor binding domain antibodies with epidemiological and clinical characteristics after immunization with the 1st and 2nd doses of the BNT162b2 vaccine","author":"A Michos","year":"2021","journal-title":"Vaccine"},{"key":"pone.0266958.ref014","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1080\/22221751.2021.1953403","article-title":"Antibody titres decline 3-month post-vaccination with BNT162b2","volume":"10","author":"J Favresse","year":"2021","journal-title":"Emerging Microbes & Infections"},{"key":"pone.0266958.ref015","article-title":"Decline of antibody titres 3 months after two doses of BNT162b2 in non-immunocompromised adults","author":"A Erice","year":"2021","journal-title":"Clin Microbiol Infect"},{"key":"pone.0266958.ref016","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Core Team","year":"2018"},{"key":"pone.0266958.ref017","unstructured":"Hadley Wickham, Romain Francois, Lionel Henry, Kirill Muller. dplyr: A Grammar of Data Manipulation; 2021. https:\/\/CRAN.R-project.org\/package=dplyr."},{"key":"pone.0266958.ref018","unstructured":"Hadley Wickham. tidyr: Tidy Messy Data; 2021. https:\/\/CRAN.R-project.org\/package=tidyr."},{"key":"pone.0266958.ref019","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-24277-4","volume-title":"ggplot2: Elegant Graphics for Data Analysis","author":"Hadley Wickham","year":"2016"},{"key":"pone.0266958.ref020","doi-asserted-by":"crossref","unstructured":"Matthias Kohl. MKinfer: Inferential Statistics; 2020. http:\/\/www.stamats.de.","DOI":"10.32614\/CRAN.package.MKinfer"},{"key":"pone.0266958.ref021","first-page":"1","article-title":"Fitting Linear Mixed-Effects Models Using lme4","volume":"67","author":"Douglas Bates","year":"2015","journal-title":"J Stat Soft"},{"key":"pone.0266958.ref022","first-page":"1","article-title":"lmerTest Package: Tests in Linear Mixed Effects Models","volume":"82","author":"Alexandra Kuznetsova","year":"2017","journal-title":"J Stat Soft"},{"key":"pone.0266958.ref023","first-page":"1","article-title":"robustlmm: An R Package for Robust Estimation of Linear Mixed-Effects Models","volume":"75","author":"Manuel Koller","year":"2016","journal-title":"J Stat Soft"},{"key":"pone.0266958.ref024","unstructured":"Russell V. Lenth. emmeans: Estimated Marginal Means, aka Least-Squares Means; 2021. https:\/\/CRAN.R-project.org\/package=emmeans."},{"key":"pone.0266958.ref025","doi-asserted-by":"crossref","first-page":"3139","DOI":"10.21105\/joss.03139","article-title":"performance: An R Package for Assessment, Comparison and Testing of Statistical Models","volume":"6","author":"Daniel Ludecke","year":"2021","journal-title":"JOSS"},{"key":"pone.0266958.ref026","unstructured":"Rogier Kievit & Sacha Epskamp. Simpsons: Detecting Simpson\u2019s Paradox; 2012. https:\/\/CRAN.R-project.org\/package=Simpsons."},{"key":"pone.0266958.ref027","unstructured":"Kamil Barton. MuMIn: Multi-Model Inference; 2020. https:\/\/CRAN.R-project.org\/package=MuMIn."},{"key":"pone.0266958.ref028","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1111\/2041-210X.12504","article-title":"simr: an R package for power analysis of generalised linear mixed models by simulation","volume":"7","author":"Peter Green","year":"2016","journal-title":"Methods Ecol Evol"},{"key":"pone.0266958.ref029","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing","volume":"57","author":"Y Benjamini","year":"1995","journal-title":"Journal of the Royal Statistical Society: Series B (Methodological)"},{"key":"pone.0266958.ref030","unstructured":"Schweinberger M. Fixed- and Mixed-Effects Regression Models in R. Troms\u00f8; 2021."},{"key":"pone.0266958.ref031","volume-title":"An introduction to categorical data analysis","author":"A. Agresti","year":"2018"},{"key":"pone.0266958.ref032","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1111\/2041-210X.13434","article-title":"Robustness of linear mixed\u2010effects models to violations of distributional assumptions","volume":"11","author":"H Schielzeth","year":"2020","journal-title":"Methods Ecol Evol"},{"issue":"Suppl 3","key":"pone.0266958.ref033","doi-asserted-by":"crossref","first-page":"S114","DOI":"10.1093\/infdis\/jiu066","article-title":"Sex-based biology and the rational design of influenza vaccination strategies","volume":"209","author":"SL Klein","year":"2014","journal-title":"Journal of Infectious Diseases"},{"key":"pone.0266958.ref034","doi-asserted-by":"crossref","first-page":"E257","DOI":"10.1002\/ajh.26185","article-title":"Age-dependent and gender-dependent antibody responses against SARS-CoV-2 in health workers and octogenarians after vaccination with the BNT162b2 mRNA vaccine","volume":"96","author":"E Terpos","year":"2021","journal-title":"Am J Hematol"},{"key":"pone.0266958.ref035","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/S0140-6736(21)01642-1","article-title":"Spike-antibody waning after second dose of BNT162b2 or ChAdOx1","volume":"398","author":"M Shrotri","year":"2021","journal-title":"The Lancet"},{"key":"pone.0266958.ref036","doi-asserted-by":"crossref","unstructured":"Nace DA, Kip KE, Palmer OMP, Shurin MR, Mulvey K, Crandall M, et al. Antibody Responses in Elderly Residential Care Persons following COVID-19 mRNA Vaccination.; 2021.","DOI":"10.1101\/2021.04.07.21254925"},{"key":"pone.0266958.ref037","first-page":"100208","article-title":"Dynamics of antibody response to BNT162b2 vaccine after six months: a longitudinal prospective study","volume":"2021","author":"P Naaber","journal-title":"The Lancet Regional Health\u2014Europe"},{"key":"pone.0266958.ref038","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1038\/s41467-021-21444-5","article-title":"Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19","volume":"12","author":"AK Wheatley","year":"2021","journal-title":"Nat Commun"},{"key":"pone.0266958.ref039","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.3390\/vaccines9091042","article-title":"Age and Smoking Predict Antibody Titres at 3 Months after the Second Dose of the BNT162b2 COVID-19 Vaccine","volume":"9","author":"Y Nomura","year":"2021","journal-title":"Vaccines"},{"key":"pone.0266958.ref040","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1164\/arrd.1971.104.3.368","article-title":"Cigarette smoking and hemagglutination inhibition response to influenza after natural disease and immunization","volume":"104","author":"JF Finklea","year":"1971","journal-title":"Am Rev Respir Dis"},{"key":"pone.0266958.ref041","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/S0264-410X(98)00213-8","article-title":"The effect of smoking on influenza, influenza vaccination efficacy and on the antibody response to influenza vaccination","volume":"17","author":"M Cruijff","year":"1999","journal-title":"Vaccine"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0266958","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,23]],"date-time":"2024-09-23T10:15:10Z","timestamp":1727086510000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0266958"}},"subtitle":[],"editor":[{"given":"Patricia Evelyn","family":"Fast","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,4,29]]},"references-count":41,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4,29]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0266958","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,29]]}}}